Adjunctive Pharmacotherapy: What's Nice, What's Necessary?

Paul W. Armstrong, MD
University of Alberta
Edmonton, Canada


Dr. Armstrong focused on novel therapies rather than established agents such aspirin and beta blocking drugs: He discussed anti-thrombin/anti-platelet strategies and anti-inflammatory strategies, as well as agents and multiple-drug regimens that employ both approaches to reduce cellular damage and inflammation associated with reperfusion procedures. In addition, he noted agents that may have future roles in treating patients with ST-segment elevation presentations such as stents with new drugs, adenosine, and complement inhibitors. In summary, he advocated a view of "pharmaco-invasive" treatment in which different classes of drugs play an integral part in improving the success rate of invasive reperfusion techniques.

Dr. Armstrong opened by presenting a model of contributors to unstable coronary syndromes, including hemodynamic, hematologic, infectious, inflammatory, lipid, and metabolic factors. He noted that in the course of his presentation he would present hypotheses and trial data on agents that may act effectively as adjunctive pharmacotherapy with reperfusion techniques through intervention on one or more contributing factors.

He said that there are four general goals for adjunctive agents: enhancing the success rate of mechanical procedures, minimizing their risks, protecting myocardium from ischemia before and during a procedure, and retarding or reversing the disease itself. He discussed 2 groups of patients with acute coronary syndromes, those who presented with non-ST-segment elevation and those presenting with ST-segment elevation.

First, he discussed strategies for patients with non-ST-segment presentations. One approach to adjunctive therapy is use of an anti-thrombin agent before or during reperfusion, or during both periods. He mentioned one trial whose data were first presented at the current conference (REPLACE II), in which anti-thrombin therapy (through a glycoprotein IIb/IIIa inhibitor) was tested as an adjunct to stent placement and aspirin use. Although new data such as these will require time for analysis and interpretation, Dr. Armstrong believes they support a model in which generation of thrombin itself may be prevented through a type of drug that can generally be described as a "tissue factor inhibitor agent."

Abciximab is a glycoprotein IIb/IIIa inhibitor that has been studied in published trials: Results indicate that it produces improvement in outcome (myocardial infarction or death) when used before angioplasty and shows an amplified, larger benefit when continued after the procedure is completed. Although they need to be interpreted with caution, Dr. Armstrong believes that raw registry data showing a correlation between early use of a glycoprotein IIb/IIIa inhibitor and decreased in-hospital mortality should be discussed with caution, the data support the hypothesis that this approach to therapy is promising.

He then turned to a discussion on the role of a combined aspirin/clopidogrel regimen as an adjunct to angioplasty (cited trials are PCI-CURE and CREDO, latter presented at this conference), noting that the published literature shows a 31% risk reduction 1 year after treatment in the composite outcome of death or myocardial infarction.

As a summary to the first part of his presentation, Dr. Armstrong put out the following as a revised guideline for care of patients with non-ST-segment elevation syndromes: use of a glycoprotein IIb/IIIa inhibitor, aspirin, clopidogrel, and an anti-thrombin component as pre-reperfusion procedure adjunctive therapy. He noted that further research will clarify the relative value of each component, as well as the cost-effectiveness of drugs and combination regimens.

The second part of his presentation centered on novel therapies for use with patients presenting with ST-segment elevation acute coronary syndromes. He discussed four therapies: use of a stent plus abciximab, adenosine, the combination of glucose, insulin, and potassium, or use of a complement inhibitor.

Dr. Armstrong started with use of a stent plus abciximab, noting that the investigators of the ADMIRAL study have presented extended results showing maintenance of advantage through 3 years of follow-up.

Adenosine has potential for reversing regions of no re-flow, as well as decreasing risk for Q-wave myocardial infarction, recurrent infarction, heart failure, and death. However, statistically significant data have not yet been published, which means its potential as an adjunct therapy is unclear.

Complement inhibitors have also been explored. Findings from the CARDINAL program were presented at the current conference. Although there was no difference in the primary outcome, size of infarct, with use of a complement inhibitor, there was a significant decrease in mortality after angioplasty with use of the trial agent. Such findings mandate larger trials and reopen the question of the mechanism or mechanisms through which these anti-inflammatory agents affect outcome.

Before closing, Dr. Armstrong noted 3 ongoing studies whose results may bring some clarity to the question of adjunctive pharmacotherapy: the Finesse study, which will compare abciximab-facilitated reperfusion against reteplase and abciximab-facilitated reperfusion, the Advance MI study, which will examine a possible role for eptifibatide in the Emergency Room, and the ASSENT 4 study, which will look at the role of a thrombolytic agent (in conjunction with aspirin and unfractionated heparin) as an adjunct for reperfusion.

Dr. Armstrong closed with a slide that applies to reperfusion by fibrinolysis, angioplasty, or stent placement. The sides of the triangle represent 3 types of pharmacologic intervention: anticoagulation, anti-inflammatory, and disease regression (the last through agents such as statins).


Reporter: Elizabeth Coolidge-Stolz, MD